5-fluorouracil derivatives useful as carcinostatic substances

ABSTRACT

A novel 5-fluorouracil derivative of the formula: ##STR1## wherein R 1  is a fluorine-containing C 1  -C 10  organic group which optionally contains sulfur, oxygen and/or nitrogen. The novel 5-fluorouracil derivative is useful as a carcinostatic substance, which has a high carcinostatic activity but which is less toxicity against digestive tract and causes less autonomic imbalance than other known 5-fluorouracil derivatives.

BACKGROUND OF THE INVENTION

1. Field of the Invention

The present invention relates to novel 5-fluorouracil derivatives, whichare useful as carcinostatic substances.

2. Discussion of Related Art

5-Fluorouracil is known as a antimetabolite having a broad-spectrumantitumor activity and used in clinical therapy. However, it is highlytoxic when orally administered and particularly accompanied with sideeffects such as disorders in the gastrointestinal.

To solve such drawbacks of 5-fluorouracil, many derivatives of5-fluorouracil have been proposed. One of the early developedderivatives is 1-(2-tetrahydrofuryl)-5-fluorouracil. Although thiscompound is less toxic, its carcinostatic activity is weak so that it isnot a satisfactory carcinostatic substance (cf. "Gan to Kagakuryouhou"(Cancer and Chemotherapy), 8, No. 11, 1811 (1981)).

To maintain the strong activity on one hand and to decrease the toxicityof 5-fluorouracil on the other hand, studies of the derivatives of5-fluorouracil have been made. As a result, for example,1-hexylcarbamoyl-5-fluorouracil was developed. This derivative is moresuitable than the previous derivatives for oral administration, since ithas stronger carcinostatic activity and lower toxicity against thegastrointestinal. However, since the metabolites produced from1-hexylcarbamoyl-5-fluorouracil by the oxidation of the hexyl group in aliver causes autonomic imbalances such as frequency of feces, heatsensation and pollakiuria which are not found in the use of other5-fluorouracil derivatives, as a practical matter, this derivativeshould be used together with a tranquilizer (cf. Pharmacia, 16, No. 6,524-527 (1980)).

SUMMARY OF THE INVENTION

An object of the present invention is to provide novel 5-fluorouracilderivatives which are useful as carcinostatic substances having highactivity but less toxicity.

Another object of the present invention is to provide novel5-fluorouracil derivatives which cause less side effects such asdisorders in the digestive tracts and autonomic imbalance.

Accordingly, the present invention provides a novel derivative of theformula: ##STR2## wherein R¹ is a fluorine-containing C₁ -C₁₀ organicgroup which optionally contains sulfur, oxygen and/or nitrogen.

DETAILED DESCRIPTION OF THE INVENTION

Among the 5-fluorouracil derivatives (I) of the present invention,preferred are those in which R¹ is a group of the formula:

    --(CH.sub.2).sub.h --CH(R.sup.2)--CF.sub.3

wherein R² is hydrogen or a C₁ -C₄ aliphatic group, and h is an integerof 0 to 4; a group of the formula:

    --CH.sub.2 --(CR.sup.3.sub.2).sub.i --CHF.sub.2

wherein R³ is hydrogen or fluorine, and i is an integer of 0 to 5; or agroup of the formula:

    --(CH.sub.2).sub.j --CHF(R.sup.4)

wherein R⁴ is hydrogen or methyl, and j is an integer of 1 to 4, sincethese preferred derivatives have large therapeutic indexes (TI) and/orcauses less autonomic imbalance. Preferred examples of the group R¹ are--CH₂ CF₃, --(CH₂)₂ CF₃, --(CH₂)₃ CF₃, --(CH₂)₄ CF₃, --(CH₂)₅ CF₃, --CH₂CH(CH₃)CF₃, --CH₂ CH(C₂ H₅)CF₃, --CH₂ CH(C₃ H₇)--CF₃, --CH₂ CH(C₄H₉)CF₃, --(CH₂)₂ CH(CH₃)CF₃, --CH₂ CHF₃, --(CH₂)₂ --CHF₂, --(CH₂)₃ CHF₂,--(CH₂)₄ CHF₂, --(CH₂)₅ CHF₂, --(CH₂)₄ CH₂ F, --(CH₂)₄ CHFCH₃ and--(CH₂)₂ NHC(═O)CH₂ SCHF.sub. 2. Among them, --(CH₂)₂ CF₃, --(CH₂)₃ CF₃,--CH₂ CH(CH₃)CF₃, --(CH₂)₂ CH(CH₃)CF₃ and --(CH₂)₅ CHF₂ are morepreferred.

The 5-fluorouracil derivative (I) of the present invention may beprepared by following methods (i) or (ii):

Method (i):

5-Fluorouracil is successively reacted, with phosgene (COCl₂) and afluorine-containing amine of the formula:

    NH.sub.2 R.sup.1                                           (II)

wherein R¹ is the same as defined above, as follows: ##STR3## wherein R¹is the same as defined above.

The first reaction of 5-fluorouracil with phosgene is effected bydissolving 5-fluorouracil in an organic base (e.g. pyridine,triethylamine and methylmorpholine) and blowing 1.2 to 2 equivalents ofphosgene in the solution of 5-fluorouracil with cooling at -10° to +10°C. The second reaction with the fluorine-containing amine is effected byadding 1 to 1.5 equivalents of said amine to the reaction mixture of5-fluorouracil and phosgene at -10° to +10° C.

The fluorine-containing amine (II) may be prepared by, for example,converting a hydroxyl group and chlorine of a compound having thehydroxyl group and chlorine to fluorine and the amine group,respectively (cf. Bull. Chem. Soc. Jpn, 51, 1267 (1978) and Angew. Chem.Int. Ed., 7, 919 (1968)), or reducing a fluorine-containing primaryamide with sodium borohydride or lithium aluminum hydride (cf.Tetrahedron Lett., 1969, 4555).

Method (ii):

A fluorine-containing carboxylic acid of the formula:

    R.sup.1 COOH                                               (III)

wherein R¹ is the same as defined above is reacted withdiphenylphosphoryl azide to obtain an isocyanate of the formula:

    OCN--R.sup.1                                               (IV)

wherein R¹ is the same as defined above and reacting the isocyanate (IV)with 5-fluorouracil to obtain the 5-fluorouracil derivative (I) of thepresent invention.

The fluorine-containing carboxylic acid (III) can be prepared by themethod described in J. Am. Chem. Soc., 76 3722 (1954).

When the fluorine-containing carboxylic acid (III), diphenylphosphorylazide and 5-fluorouracil are mixed and heated in an organic solvent, theabove two reactions proceed successively, it is not necessary to carryout these reactions stepwise. Examples of the organic solvent arepyridine, triethylamine, dimethylacetamide, dimethylformamide andmixtures thereof. Usually, the reaction temperature is from 10° to 110°C., and the reaction time is from 1 to 10 hours. The fluorine-containingcarboxylic acid is used in an amount of 1 to 1.5 moles per mole of5-fluorouracil, and diphenylphosphoryl azide is used in an amount of 1to 1.5 moles per mole of 5-fluorouracil.

The present invention will be illustrated by following examples.

EXAMPLES 1-13

To a cold solution of 5-fluorouracil (2.6 g, 0.02 mole) in pyridine (50ml) at -3° to +2° C., phosgene which is generated by droppingtrichloromethyl chloroformate onto activated carbon (4 g, 0.02 mole) isintroduced. After purging unreacted phosgene by blowing nitrogen in themixture, a fluorine-containing amine shown in Table 1 (0.02 mole) isadded to the mixture cooled at -5° C. and stirred at the sametemperature for one hour and then at room temperature for 30 minutes.

After concentrating the reaction mixture under reduced pressure, ethylacetate (200 ml) and 1N hydrochloric acid (50 ml) are added and stirred.Materials precipitated are filtrated off. The filtrate (the ethylacetate phase) is recovered and evaporated to dryness under reducedpressure followed by purification by column chromatography using silicagel.

The fluorine-containing amine used, the R¹ group contained in theproduct, a yield of the product, results of ¹ H- and ¹⁹ F-NMR analysesof the product, ILS (%) and TI are shown in Table 1.

The ILS and TI have common meanings in this field and are measuredaccording to the methods described in Chem. Pharm. Bull., 26, No. 1,161-165 (1978) in which used are BDF type mice (female) (5 mice pergroup, an average weight of 16±2 g) inplanted by 1×10⁵ cells oflymphocytic leukemia L-1210 (National Cancer Institute type) and theproduct is orally administered.

EXAMPLES 14-17

To a mixture of dimethylformamide (15 ml), 5-fluorouracil (1 g, 7.7mmol), diphenylphosphoryl azide (2.2 g, 8 mmol) and triethylamine (5.1g, 50 mmol), a fluorine-containing carboxylic acid shown in Table 2 (8mmol) is added and reacted at 80° C. for 2 hours.

After cooling, the reaction mixture is concentrated under reducedpressure. To the concentrated mixture, ethyl acetate (100 ml) and 1Nhydrochloric acid (50 ml) are added and stirred. Materials precipitatedare filtrated off. The filtrate (the ethyl acetate phase) is recoveredand evaporated to dryness under reduced pressure followed bypurification by column chromatography using silica gel with a mixedsolvent of chloroform and ethanol in a volume ratio of 10:1. Thefluorine-containing carboxylic acid, the R¹ group contained in theproduct, a yield of the product, results of ¹ H- and ¹⁹ F-NMR analysesof the product, ILS (%) and TI are shown in Table 2.

As a solvent in the NMR analyses of the compounds, CDCl₃ is used inExamples 6, 8, 10, 11, 13, 16 and 17, and (CD₃)₂ SO is used in otherExamples. In ¹⁹ F-NMR, trifluoroacetic acid is an external standard.

For evaluation of suppression of autonomic imbalance by the compound ofthe present invention, according to the descriptions of "Rinsho-yakuri"(Clinical pharmacology), 11, No. 1, 17 and 27 (1980), (1) action onneutrons in a pretaminar part of the optic nerve which is a center forregulation of the body temperature of rats and outside said part (adegree of caumesthesia) and (2) action on bladder movement of cats(frequency of uresiesthesia) are examined. From the results of theseexaminations, the compound having the R¹ group selected from the groupconsisting of --(CH₂)₂ --CF₃, --(CH₂)₃ CF₃, --CH₂ CH(CH₃)CF₃, --(CH₂)₂CH(CH₃)CF₃ and --(CH₂)₄ CHF₂ are found to have better effects.

COMPARATIVE EXAMPLES 1 AND 2

With a compound (I) wherein R¹ is --(CH₂)₅ CH₃ (Comparative Example 1)or --CH₂ (CF₂)₂ CF₃ (Comparative Example 2), ILS and TI are measured.The results are shown in Table 3.

                                      TABLE 1    __________________________________________________________________________    Ex-    am-       F-containing                R.sup.1                       Yield                           .sup.1 H--NMR                   ILS (%)    ple       amine    group  (%) (ppm)              .sup.19 F--NMR                                                           (Dose.sup.1)                                                                TI    __________________________________________________________________________    1  NH.sub.2 CH.sub.2 CF.sub.3                --CH.sub.2 CF.sub.3                       52  4-4.4 (2H, m), 8.45 (1H, d, J=7 Hz),                                              -8.0 (3F, t, J=8.6                                                           79                                                                2.50)                           9.62 (1H, m), 12.4 (1H, bs)                                              85.8 (1F, d, J=7 Hz)    2  NH.sub.2 (CH.sub.2).sub.3 --                --(CH.sub.2).sub.3 --                       62  1.7-2.05 (2H, m), 2.15-2.6 (2H, m),                                              -13.8 (3F, t,                                                           55                                                                10.0)       CF.sub.3 CF.sub.3   3.3-3.65 (2H, m), 8.5 (1H, d, J=7                                              Hz), 86.9 (1F, d, J=7.1                           9.35 (1H, m), 12.5 (1H, bs)                                              Hz)    3  NH.sub.2 (CH.sub.2).sub.2 --                --(CH.sub.2).sub.2 --                       72  1.25 (3H, d, J=7.1 Hz), 1.4-2.1 (3H,                                              -6.6 (3F, d, J=11.5                                                           76                                                                5.00)       CH(CH.sub.3)CF.sub.3                CH(CH.sub.3)--                           m), 3.4-3.7 (2H, m), 8.5 (1H, d,                                              86.9 (1F, d, J=7 Hz)                CF.sub.3   7.5 Hz), 9.25-9.45 (1H, m), 12.4                           (1H, bs)    4  NH.sub.2 CH.sub.2 CHF.sub.2                --CH.sub.2 CHF.sub.2                       56  3.85 (2H, m), 6.3 (1H, tt, J=5.7                                              44.2 (2F, dt, J=17                                                           59                                                                5.00)                           J=57 Hz), 8.55 (1H, d, J=8.5 Hz),                                              J=57 Hz), 86.1 (1F, d,                           9.55 (1H, m), 12.5 (1H, bs)                                              J=7.1 Hz)    5  NH.sub.2 (CH.sub.2).sub.4 --                --(CH.sub.2).sub.4 --                       61  1.4-2.1 (4H, m), 2.5-2.8 (2H, m),                                              37.2 (2F, dt, J=17                                                           35                                                                3.00)       CHF.sub.2                CHF.sub.2  3.3-3.6 (2H, m), 5.85 (1H, tt, J=5.7                                              J=57 Hz), 84.3 (1F, d,                           Hz, J=57.1 Hz), 8.45 (1H, d, J=7.1                                              J=7.1 Hz)                           Hz), 9.35 (1H, bs), 12.3 (1H, bs)    6  NH.sub.2 (CH.sub.2).sub.5 --                --(CH.sub.2).sub. 5 --                       61  1.2-2.05 (8H, m), 3.5-3.6 (2H, q,                                              37.2 (2F, dt, J=17                                                           58                                                                10.0)       CHF.sub.2                CHF.sub.2  J=5.7 Hz), 5.85 (1H, tt, J=5.4 Hz,                                              J=57 Hz), 83.4 (1F, m)                           J=57 Hz), 8.5 (1H, d, J=7 Hz),                           9.05 (2H, bs)    7  NH.sub.2 CH.sub.2 CF.sub.2 --                --CH.sub.2 CF.sub.2 --                       45  3.6-4.4 (2H, m), 6.5 (1H, tt, J=51                                              85.9 (1F, d, J=8.5                                                           57                                                                3.60)       CF.sub.2 H                CHF.sub.2  Hz, 5.7 Hz), 8.5 (1H, d, J=7.1 Hz),                                              59.7 (2F, m),                           9.6 (1H, m), 12.5 (1H, bs)                                              43.7-44.3 (2F, m)    8  NH.sub.2 CH.sub.2 (CF.sub.2 --                --CH.sub.2 (CF.sub.2 --                       50  3.95-4.2 (2H, m), 6.1 (1H, tt, J=51                                              82.0 (1F, d, J=5.7                                                           62                                                                3.30)       CF.sub.2).sub.2 H                CF.sub.2).sub.2 H                           Hz, 5.7 Hz), 8.5 (1H, d, J=5.7 Hz),                                              39.3 (2F, m), 46.4 (2F,                           8.65 (1H, bs), 9.55 (1H, bs)                                              m), 50.8 (2F, m), 58.3                                              (2F, m)    9  NH.sub.2 CH.sub.2 (CF.sub.2 --                --CH.sub.2 (CF.sub.2 --                       48  4-4.6 (2H, m), 7.3 (1H, tt, J=51                                              85.7 (1F, d, J=7.1                                                           29                                                                --00)       CF.sub.2).sub.3 H                CF.sub.2).sub.3 H                           5.7 Hz), 8.5 (1H, d, J=8.3 Hz),                                              38.8 (2F, m), 43.4 (2F,                           9.7 (1H, m), 12.5 (1H, bs)                                              m), 44.7 (4F, m), 50.4                                              (2F, m), 59.8 (2F, m)    10 NH.sub.2 (CH.sub.2).sub.4 --                --(CH.sub.2).sub.4 --                       60  1.2-1.8 (10H, m), 3.42 (2H, t, J=                                              83.5 (1F, d, J=8.6                                                           54                                                                3.00)       CHFCH.sub.3                CHFCH.sub.3                           5.7 Hz), 8.43 (1H, d, J=6 Hz),                                              94.4 (1F, m)                           8.8-9.1 (2H, bm),    11 NH.sub.2 (CH.sub.2).sub.4 --                --(CH.sub.2).sub.4 --                       56  1.3-2 (6H, m), 3.4 (2H, t, J=5.7                                              83.5 (1F, d, J=5.7                                                           51                                                                3.50)       CH.sub. 2 F                CH.sub.2 F 4.45 (2H, dt, J=46 Hz, 5.7 Hz), 8.45                                              139.9 (1F, tt, J=46 Hz,                           (1H, d, J=6 Hz), 8.8-9.3 (2H, bm)                                              23 Hz)    12 NH.sub.2 (CH.sub.2).sub.5 --                --(CH.sub.2).sub.5 --                       53  1.3-1.9 (6H, m), 2.0-2.3 (2H, m),                                              -11.5 (3F, t,                                                           60                                                                3.50)       CF.sub.3 CF.sub.3   3.3-3.5 (2H, m), 8.5 (1H, d, J=6                                              Hz), 84.2 (1F, d, J=                           8.6 (1H, bs), 9.1 (1H, bs)                                              7 Hz)    13 NH.sub.2 CH.sub.2 CH.sub.2 --                --CH.sub.2 CH.sub.2 --                       60  3.4-3.8 (6H, m), 7.55 (1H, t, J=57                                              15.2 (2F, d, J=57                                                           53                                                                3.00)       NHC(═O)CH.sub.2 --                NHC(═O)--                           Hz), 8.5 (1H, m), 8.6 (1H, d, J=8.5                                              86.6 (1F, d, J=5.7 Hz)       SCF.sub.2 H                CH.sub.2 SCHF.sub.2                           Hz), 9.4 (1H, m), 12.55 (1H, bs)    __________________________________________________________________________     Note: .sup.1 mg/kg/day.

                                      TABLE 2    __________________________________________________________________________        F-containing    Exam-        carboxylic                 R.sup.1                        Yield                            .sup.1 H--NMR                  ILS (%)    ple acid     group  (%) (ppm)              .sup.19 F--NMR                                                           (Dose.sup.1)                                                                TI    __________________________________________________________________________    14  CF.sub.3 CH.sub.2 CH.sub.2 --                 --CH.sub.2 CH.sub.2 --                        48  2.55-2.95 (2H, m), 3.6-3.85 (2H,                                               -14.7 (3F, t,                                                           85                                                                7.10)        COOH     CF.sub.3   8.6 (1H, d, J=7.1 Hz), 9.5 (1H,                                               Hz), 86.4 (1F, d,                            12.5 (1H, bs)      J=7.5 Hz    15  CF.sub.3 CH(CH.sub.3)--                 --CH.sub.2 CH--                        65  1.2 (3H, d, J=7.1 Hz), 3.2-3.85                                               -7.2 (3F, d, J=8.5                                                           62                                                                12.0)        CH.sub.2 COOH                 (CH.sub.3)CF.sub.3                            m), 8.45 (1H, d, J=7.5 Hz), 9.5                                               84.7 (1F, d, J=7.5 Hz)                            m), 12.55 (1H, bs)    16  CF.sub.3 CH(CH.sub.2 --                 --CH.sub.2 CH--                        52  1.1 (3H, t, J=8.5 Hz), 1.5-2.1 (3H,                                               -9.1 (3F, d, J=8.6                                                           40                                                                3.00)        CH.sub.3)CH.sub.2 COOH                 (CH.sub.2 CH.sub.3)--                            m), 3.5-3.8 (2H, m), 8.5 (1H, d,                                               82.9 (1F, d, J=7.1 Hz)                 CF.sub.3   7.5 Hz), 8.6 (1H, bs), 9.3 (1H, bs)    17  CF.sub.3 CH(CH.sub.2 --                 --CH.sub.2 CH--                        45  0.95 (3H, d, J=5.7 Hz), 1.2-1.9                                               -8.9 (3F, d, J=11.4                                                           53                                                                2.70)        CH.sub.2 CH.sub.2 CH.sub.3)--                 (CH.sub.2 CH.sub.2 --                            m), 2.4 (1H, bs), 3.55-3.75 (2H,                                               82.9 (1F, d, J=14.3 Hz)        CH.sub.2 COOH                 CH.sub.2 CH.sub.3)--                            8.5 (1H, d, J=7.5 Hz), 9.1 (1H, bs),                 CF.sub.3   9.35 (1H, m)    __________________________________________________________________________

                  TABLE 3    ______________________________________    Comparative    ILS (%)    Example No.    (Dose: mg/kg/day)                                 TI    ______________________________________    1              70 (300)      4.3    2              61 (100)      2.0    ______________________________________

What is claimed is:
 1. A 5-fluorouracil derivative of the formula:##STR4## wherein R¹ is is selected from the group consisting of --(CH₂)₃CF₃, --(CH₂)₅ CHF₂, --CH₂ CH(CH₃)CF₃ and --CH₂ CH₂ CF₃.
 2. The5-fluorouracil derivative according to claim 1, wherein R¹ is --(CH₂)₃CF₃.
 3. The 5-fluorouracil derivative according to claim 1, wherein R¹is --(CH₂)₅ CHF.
 4. The 5-fluorouracil derivative according to claim 1,wherein R¹ is --CH₂ CH(CH₃)CF₃.
 5. The 5-fluorouracil derivativeaccording to claim 1, wherein R¹ is --CH₂ CH₂ CF₃.